Alpha-1-antitrypsin (α1AT) deficiency is a genetic disorder that manifests as pulmonary emphysema and liver cirrhosis. α1AT deficiency is the most common genetic cause of liver disease in children and also an underappreciated cause of liver disease in adults. The prevalence in the general population in Western Europe is approximately 1 in 2,000. The most common and severe deficiency allele is the Z variant (two alleles mutated). This variant is characterized by the accumulation of Z-α1AT polymers in the endoplasmic reticulum of hepatocytes leading to cell death and to a severe reduction of α1AT in the serum. The latter results in a loss of its antiprotease activity and its ability to protect lung tissue. Thus far, there are only very limited therapeutic options in α1AT deficiency. A more detailed understanding of the biology governing α1AT biogenesis is required in order to identify new pharmacological agents and biomarkers. This review will present current knowledge on α1AT deficiency and focus on recent discoveries and new strategies in the treatment of this disease.